Aetiology
Amfetamine and methamphetamine are both highly addictive stimulants, which affect the central nervous system in similar ways; methamphetamine differs from amfetamine in that, at comparable doses, greater amounts of drug get into the brain, resulting in increased potency.[3] This leads to a higher potential for widespread misuse for methamphetamine compared to amfetamine.[5] Bingeing of both drugs can be associated with tachyphylaxis, in which the person requires higher doses to get the same effect. This is due to both down-regulation of the post-synaptic receptors and depletion of pre-synaptic stores of neurotransmitter.
The aetiology is unclear, although a number of predisposing factors exist, including comorbid psychiatric disorders and adverse childhood events. Psychiatric comorbidity is complex, given the overlap in symptoms (e.g., psychosis and depression) and presence of shared risk factors.[27][28]
Pathophysiology
The action of amfetamine and methamphetamine is complex and diverse.[6] They act indirectly as sympathomimetics by increasing the release and decreasing the pre-synaptic uptake of biogenic amines (i.e., dopamine, noradrenaline, and serotonin) from the synaptic cleft. In addition, they reduce intracellular destruction of these biogenic amines by inhibiting mitochondrial monoamine oxidase, further increasing availability. This biogenic amine availability stimulates both the central and peripheral nervous systems. With prolonged stimulation, post-synaptic receptor down-regulation and pre-synaptic neurotransmitter depletion occur.
Centrally, initial stimulation of the brain occurs, increasing alertness. With increased doses, agitation may occur. With neurotransmitter depletion and down-regulation of the receptors, increasing doses are needed to get the same stimulation (tolerance) and eventually a depression of neurotransmission results. If associated with days of use, significant depletion of central nervous system neurotransmitters can be seen and is usually accompanied by depression, excessive tiredness, and fatigue. Acute use of high doses can cause immediate toxicity and result in profound brain and cardiovascular alterations. Peripherally, a similar set of actions leads to sympathetic stimulation with increased pupil size, heart rate, and blood pressure. In an overdose, peripheral neurotransmitters become depleted, and vascular collapse can occur.
The exact mechanisms of amfetamine and methamphetamine use disorder are not known, but may involve stimulation of central reward pathways (i.e., dopamine neurons in the ventral tegmentum, the nucleus accumbens, and the prefrontal cortex). Patients with methamphetamine use disorder have been shown to have lower scores in five cognitive domains (processing speed, attention, verbal learning, visual learning, and problem-solving) in addition to white matter microstructure changes.[29] Methamphetamine has longer-lasting and more severe adverse effects on the central nervous system than amfetamine.[4] The impact of methamphetamine on cognition is the subject of intense debate; it is difficult to assess whether observed cognitive impairments are pre-existing, due to exposure, or due to behaviours associated with substance use disorder.[6][30] There is evidence that cognition is negatively affected to some degree even after prolonged abstinence from methamphetamine.[31] Changes associated with methamphetamine use disorder have been likened to an altered brain state that is consistent with those seen in degenerative central nervous system diseases.[6] Chronic high-dose exposure to amfetamines is associated with a number of structural brain changes on neuroimaging, including widespread grey and white matter alterations, particularly affecting the frontostriatal system, and prominent reductions in the left superior temporal gyrus and right inferior parietal lobe.[32][33][34]
Methamphetamine-induced chronic neurotoxicity appears to be associated with reactive oxygen and nitrogen species interacting with mitochondrial membranes. The resultant change in mitochondrial membranes and disruption of electron transport are thought to contribute to neuronal cell death and apoptosis.[35] The complex molecular dysregulation seen in methamphetamine and amfetamine use disorder represents an opportunity to develop novel and targeted pharmacological treatments; however, attempts to date have been unsuccessful.[6]
Classification
Diagnostic and statistical manual of mental disorders, fifth edition, text revision (DSM-5-TR)[1]
The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR) classifies amfetamine and methamphetamine as "amphetamine-type substances" and lists their respective use disorders under the subheading of stimulant use disorders. Stimulant use disorders may be mild, moderate, or severe depending on the number of symptoms within a 12-month period.[1]
Acute toxicity and long-term use
The acute or immediate toxicity with an overdose is associated with a high or excessive acute drug intake; the manifestations are often exaggerated effects of normal effects of the drug. This action phase is associated with long periods without food or sleep, followed by a reaction or recovery phase characterised by exhaustion and fatigue giving way to long periods of sleep and periods of extreme hunger.
Consequences of long-term use (e.g., stimulant use disorder) may be substance-related legal problems; depression; inability to fulfil occupational, family, or social obligations; and continued use despite danger to self or destructive effects on quality of life.
This topic covers the diagnosis and management of amfetamine and methamphetamine use disorder. For the management of acute amfetamine toxicity, please see Amfetamine overdose.
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